Terlipressin-Induced Hyponatremic Seizures in a Patient With Congenital Hepatic Fibrosis

Abstract

Introduction

Acute variceal bleeding from portal hypertension is one of the most serious complications with a mortality rate of 15% to 25%. Terlipressin is a vasopressor that controls variceal bleeding by lowering the portal pressure and reducing blood flow to the varices.

Case Presentation

We report a case of a patient with acute variceal bleeding, treated endoscopically and with terlipressin, who developed severe hyponatremia and seizures requiring admission to intensive care. Clinical and biochemical improvements were noticeable upon the cessation of terlipressin, with an eventual discharge from the hospital.

Conclusion

Prompt management of acute variceal bleeding with both endoscopic and medical interventions is required. Regular biochemical monitoring is necessary while a patient is on terlipressin treatment. The duration of treatment with terlipressin should not be prolonged unnecessarily.

Introduction

We present a case of a young patient diagnosed with congenital hepatic fibrosis who developed acute variceal bleeding and was treated with endoscopy and terlipressin. She subsequently developed severe hyponatremia and seizures, necessitating care in the intensive therapy unit (ITU).

Upper gastrointestinal bleeding is one of the commonest complications of congenital hepatic fibrosis with portal hypertension.¹ Terlipressin is a medication used to control upper gastrointestinal bleeding along with other medications and endoscopic techniques.² Rare but severe and potentially life-threatening side-effects have been linked to terlipressin use, in particular hyponatremia and seizures, with an estimated incidence of 0.1% to 1%.⁴ There are some clinical and biochemical factors that predispose to seizures secondary to hyponatremia.⁵

The aim of this report is to increase clinical awareness about the possible overlooked life-threatening complications secondary to terlipressin. The necessity for regular biochemical monitoring whilst on terlipressin without unnecessary prolongation of infusions is an important treatment consideration. Alternative vasoactive agents, such as octreotide, should be considered.⁶

Case Presentation

An 18-year-old female with a history of congenital hepatic fibrosis with portal hypertension presented to the emergency department with a 2-day history of generalized abdominal pain and 2 episodes of melaena followed by 2 episodes of severe haematemesis with clots. She was hemodynamically stable with a normal pulse and blood pressure. Prompt resuscitation was instituted with intravenous fluids (1 L ringer lactate) at 125 ml/hour, ceftriaxone 2 g intravenously, and omeprazole 40 mg intravenously. She was kept nil by mouth while the initial clinical assessment was ongoing.

The patient was on propranolol 20 mg twice daily, ursodeoxycholic acid (UDCA) 750 mg daily, and iron supplements. She was not fully compliant with her medications and admitted to an alcoholic binge a few days prior to presentation. She was a non-smoker and drank up to 2 units socially on the weekends. She never had any previous surgical interventions. Her last esophago-gastro-duodenoscopy (OGD) was performed 1-year before, which showed grade 1 oesophageal varices.

The Glasgow-Blatchford Bleeding Score, a clinical scoring system that incorporates several parameters to assess the risk of upper gastrointestinal (GI) bleed and determine further management, was 5 (2 points for raised serum urea, 1 point for the presence of melaena and 2 points for the presence of liver disease) indicating a high risk for GI bleed. Terlipressin 1 mg intravenously was commenced followed by an urgent gastroscopy. The urgent OGD revealed grade 1 esophageal varices with no signs of active or recent bleeding, but it also showed gastroesophageal varix-2 (GOV-2 varices) as per Sarin classification, which were oozing fresh blood. The remainder of the OGD was otherwise normal. Cyanoacrylate glue was injected into the visible gastric varix, and the bleeding stopped.

After the OGD, terlipressin was continued (1 mg every 6 hours). Two units of red cell concentrates were transfused in view of a hemoglobin drop to 8.6 g/dL from 13.1 g/dL. A computed tomography (CT) of her liver was later performed, which showed large spleno-renal and spleno-gastric varices with hepatofugal flow.

Twenty-nine hours after the first dose of terlipressin was given, the patient developed sudden-onset generalized tonic clonic seizures lasting around 1 minute, followed by prolonged post-ictal confusion and lethargy. Blood results showed an acute severe hyponatremia of 117 mmol/L from 135 mmol/L measured the day before (Figure 1). CT and magnetic resonance imaging (MRI) scans of her brain showed no abnormalities. An electroencephalogram (EEG) showed no focal or epileptiform features; however, the findings were compatible with non-specific encephalopathy.

Figure 1.

Changes in serum sodium levels weretracked after starting and stopping terlipressin. The normal range is between 145 mmol/L (H) and 136 mmol/L (L); values below that are considered abnormal.

She immediately was given a dose of levetiracetam 1 g intravenously and was transferred to ITU for sedation and a slow correction of serum sodium levels up to 8–10 mmol/L in 24 hours. A slow correction was required because rapid fluctuations (both a rise and fall) in serum sodium concentration can result in cerebral osmotic demyelination.

On admission to the ITU, 30 ml of 3% hypertonic saline were given over 1 hour followed by an infusion of 0.9% normal saline at 60 ml/hour. Given that the acute hyponatremia occurred in a setting of euvolemia and that the sequence of events followed the introduction of terlipressin, a diagnosis of terlipressin-induced hyponatremic seizures was made. Therefore, terlipressin was stopped. The 0.9% normal saline infusion was stopped once the serum sodium concentration reached 127 mmol/L. The sodium returned to baseline soon after, confirming the initial suspected diagnosis of drug-induced hyponatremia.

The patient had no further episodes of seizures or evidence of upper gastrointestinal bleeding, and she was transferred out of the ITU after 2 days. The remaining inpatient stay was uneventful, with no further episodes of malaena and a stable hemoglobin, and she was successfully discharged on her previous medication. No anti-epileptic medications were given. In view of a baseline low blood pressure, the propranolol dose could not be increased further. Compliance to treatment and avoidance of alcohol were emphasized.

A repeat OGD performed 2 months later showed grade 1 oesophageal varices with no signs of active or recent bleeding and non-bleeding gastric varices around the cardia. No cyanoacrylate injections or variceal banding were applied. The sodium levels remained within normal levels and no further seizures were reported.

A transjugular intrahepatic portosystemic shunt (TIPSS) was later performed due to the high risk of re-bleeding. The procedure was performed successfully with no further episodes of acute variceal bleeding.

Differential Diagnosis

The temporal association of acute hyponatremia following initiation of terlipressin is indicative of the underlying diagnosis. Nevertheless, the patient work-up investigated other causes of euvolemic hyponatremia (Tables 1 and 2). Pseudohyponatremia from hyperglycemia and dyslipidemia were excluded. Moreover, since hypothyroidism can cause hyponatremia as a result of either syndrome of inappropriate anti-diuretic hormone release (SIADH) and/or a reduction in glomerular filtration rate (GFR), a biochemical euthyroid status was also confirmed.

Table 1.

Patient Work-Up for the Investigation of Hyponatremia (Blood Test Results)

Blood test	Result	Reference range
Hemoglobin	13.1 g/dL on admission, 8.6 g/dL after 24 hours	10.8 – 13.3 g/dL
Urea	7.3 mmol/L on admission, 9.1 mmol/L after 24 hours	1.7 – 8.3 mmol/l
Platelets	128 X109/L	194 – 345 X109/L
White cell count	12.4 X109/L	4.19 – 9.43 X109/L
Bilirubin	15.8 micromol/L	0 – 21 micromol/L
Gamma glutamyl transferase	44 Units/L	5 – 36 Units/L
Alkaline phosphatase	74 Units/L	0 – 187 Units/L
Alanine aminotransferase	20 Units/L	5 – 33 Units/L
International normalized ratio	1.16	0.94 – 1.06 ratio
Albumin	40 g/L	32 – 52 g/L
Thyroid-stimulating hormone	1.546 micIU/mL	0.51 – 4.94 micIU/mL
Free thyroxine	12.96 pmol/L	10.7 – 18.4 pmol/L
Serum osmolality	256 mOsm/kg	282 – 300 mOsm/kg
Glucose	5.86 mmol/L	3.9 – 9 mmol/L
LDL cholesterol	1.16 mmol/L	0.1 – 3.88 mmol/L
Total cholesterol	3.8 mmol/L	2 – 5 mmol/L

Table 2.

Patient Work-Up for the Investigation of Hyponatremia (Urine Test Results)

Random urine test	Result	Reference range
Urine osmolality	447 mOsm/kg	50 – 1200 mOsm/kg
Sodium	44 mmol/L	54 – 190 mmol/L
Chloride	35.4 mmol/L	46 – 168 mmol/L
Potassium	36.3 mmol/L	20 – 80 mmol/L
Urine anion gap	44.9 mmol/L	−10 – 10 mmol/L

Discussion

Congenital hepatic fibrosis is a rare disease with an estimated prevalence of around 1 in 10 000 to 20 000. It is characterized by excess connective tissue in the liver and abnormalities of the portal vein which give rise to portal hypertension and varices, which may result in catastrophic upper gastrointestinal bleeds. Treatment is supportive and mainly consists of symptomatic management of complications, the most frequent of which are portal hypertension and upper GI bleeding.¹ Avoidance of further liver injury, such as alcohol, is important. These patients may need early liver transplantation.

Terlipressin, a long-acting derivative of the hormone vasopressin, is a vasoactive medication used in patients with suspected acute variceal bleed. It reduces variceal blood flow through activation of V1 receptors and vasoconstriction of the splanchnic circulation. V2 receptors that promote anti-diuresis are mostly unaffected by terlipressin, thus causing fewer fluid shifts and electrolyte imbalances than vasopressin.² Although terlipressin has a better safety profile than vasopressin, cases of hyponatremia and seizures have been reported with terlipressin use.^2,3 Given that these are rare side effects, most of the knowledge and data are only available from published case reports. Hyponatremia and seizures are known but very rare side effects of terlipressin with an incidence of 0.1% to 1%.⁴

A few mechanisms by which terlipressin causes hyponatremia have been proposed. The activation of V1 receptors redistributes blood flow from the visceral to the systemic circulation, leading to increased arterial blood pressure, increased renal perfusion, and increased urinary sodium excretion (pressure natriuresis). Terlipressin is also thought to have a partial-agonist effect on V2 receptors, resulting in increased cyclic adenosine monophosphate (cAMP) levels, which stimulate protein kinase A to activate aquaporin-2. Aquaporin channels greatly increase water permeability in the renal collecting tubule, resulting in dilutional hyponatremia.^5,7

A retrospective analysis concluded that a higher baseline serum sodium level is an independent risk factor for terlipressin-induced hyponatremia. The average decrease of serum sodium concentration was 11.19 mmol/L. Other risk factors include preserved liver function (low Child-Pugh score and low MELD score), young age, low body weight, and increased duration of terlipressin use. Increased baseline endogenous vasopressin levels in patients with liver failure can precondition the body to weaken the antidiuretic effect of terlipressin, making hyponatremia less likely.⁵

The risk of seizures increases gradually with falling serum sodium levels. It is estimated to be 2.5% with serum sodium concentration of 115 to 119 mmol/L, 5.4% between 110 and 114 mmol/L, and 11% with levels less than 110 mmol/L.⁸ To prevent complications from hyponatremia, terlipressin should not be given for more than 5 days in acute variceal bleeding.⁹ Another study suggests that 2 days of terlipressin combined with banding may be as effective as 5 days of terlipressin treatment alone. Hypotonic fluids should also be avoided in these patients.⁷ The onset of hyponatremia, with or without seizures, is variable. Therefore, serum electrolytes should be monitored for patients on terlipressin.

To our knowledge, there are at least 7 published cases of seizures from hyponatremia caused by terlipressin in adults.^2,10–15 Seizures developed 26 hours,¹⁰ 72 hours,¹¹ and 4 days² after initiation of terlipressin infusion. The first pediatric case was reported in 2013.¹⁶ Withdrawal of terlipressin was followed by a quick recovery in all cases.

Alternative and safer methods for treatment of AVB are described. The use of octreotide, a synthetic analog of somatostatin, is favored over terlipressin due to its improved control of AVB with fewer major complications. Comparing octreotide to terlipressin, Corley et al reported that octreotide was associated with a 47% lower risk of complications and a 69% lower risk of major complications and, therefore, shorter hospital stays.⁶

Conclusion

Terlipressin can be life-saving as a bridge between presentation with upper GI bleed and definitive therapeutic management. However, it does come with its risks, which can be fatal. Therefore, judicious use of this treatment is essential, and close monitoring of electrolytes is vital. Further studies about optimal monitoring strategies during terlipressin therapy and how to prevent hyponatremia in patients with potential underlying predisposing factors would be beneficial in safeguarding patient safety and enhancing clinical outcomes.